The paradoxical functions of EGFR during breast cancer progression

Abstract

The epidermal growth factor receptor (EGFR) is one of the most well-studied signaling pathways in cancer progression. As a result, numerous therapeutics including small-molecule inhibitors and monoclonal antibodies have been developed to target this critical oncogenic driver. Several of these EGFR inhibitors (EGFRi) have been evaluated in metastatic breast cancer, as high-level EGFR expression in primary tumors correlates with the highly aggressive basal-like phenotype and predicts for poor patient prognosis. Surprisingly, these trials have been unanimously unsuccessful at improving patient outcomes. Numerous factors, such as lack of proper patient selection may have contributed to the failure of these trials. However, recent findings suggest that there are fundamental changes in EGFR signaling that take place during primary tumor invasion, dissemination and ultimate metastasis of breast cancer cells. Herein, we review the outcomes of EGFR-targeted clinical trials in breast cancer and explore our current understanding of EGFR signaling within primary mammary tumors and how these events are altered in the metastatic setting. Overall, we put forth the hypothesis that fundamental changes in EGFR signaling between primary and metastatic tumors, a process we term the 'EGFR paradox,' contribute to the clinically observed inherent resistance to EGFRi. Furthermore, this hypothesis introduces the possibility of utilizing EGFR agonism as a potential therapeutic approach for the treatment of metastatic breast cancer.

Figure 1

A schematic representation of the activators, inhibitors and outcomes of EGFR signaling. EGFR is part of the four-member ErbB superfamily (ErbB1–4). These receptors form several different homo- and heterodimers (here we only depict the EGFR homodimer). EGFR is capable of binding several different extracellular ligands that agonize the receptor leading to activation of several downstream signaling events including, but no limited to those listed. Several therapeutics have been developed to antagonize EGFR including monoclonal antibodies (mAbs) that block ligand binding as well as several different kinase inhibitors. In addition to EGFR, some of these kinase inhibitors also target other ErbB receptors, supporting their use in Her2-amplified BC. All of the listed therapies are FDA approved for various cancers with the exception of Neratinib.

Figure 2

Schematic description of the EGFR paradox in primary versus metastatic BC. As tumor cells invade and disseminate, numerous selective pressures drive fundamental changes in cell signaling and growth versus death stimuli (noted by the changing colors of the tumor cells). These selective pressures and the unique microenvironment of the metastatic destination (depicted here as the lungs) yield metastatic tumors that can be quite diverse from the primary tumor. These events contribute to the listed fundamental changes in EGFR signaling in metastases as compared with primary breast tumors, constituting the ‘EGFR paradox.’ Overall, these events likely contribute to the failure of EGFRi therapies for the treatment of metastatic disease. In addition, these events point to EGFR agonism as a potential therapeutic strategy in metastatic BC.